Extracellular matrix encasement structures and methods

ABSTRACT

A bioremodelable encasement structure comprising a pouch formed from at least one sheet of bioremodelable material, the pouch including an internal region that is configured to receive a device therein, the bioremodelable material comprising mesothelial tissue.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 13/896,424,filed on May 17, 2013, which is a continuation-in-part of U.S.application Ser. No. 13/573,566, filed on Sep. 24, 2012, which is acontinuation-in-part of U.S. application Ser. No. 13/033,102, filed onFeb. 23, 2011, now U.S. Pat. No. 8,758,448, which is a continuation ofapplication Ser. No. 12/394,914, filed on Feb. 27, 2009, now abandoned,which is a continuation of application Ser. No. 11/747,004, filed on May10, 2007, now abandoned.

FIELD OF THE INVENTION

The present invention relates to implantable devices. More particularly,the present invention relates to implantable structures and devices;particularly, medical devices, encased in extracellular matrix (ECM)based pouches and/or include ECM based coatings that effectuatemodulated healing of damaged tissue and regeneration of new tissuestructures with site-specific structural and functional properties.

BACKGROUND OF THE INVENTION

As is well known in the art, treatment of various medical conditionscommonly involves implantation of medical devices and/or insertion ofmedical instruments into a body. Illustrative is the implantation ordeployment of heart valves to regulate the flow of blood throughcardiovascular vessels, and pacemakers to control abnormal heartrhythms.

Implantable medical devices; particularly, cardiovascular implants, haveunique blood biocompatibility requirements to ensure that the device isnot rejected (as in the case of natural tissue materials for heartvalves and grafts for heart transplants) or that adverse thrombogenic(clotting) or hemodynamic (blood flow) responses are avoided.

Several cardiovascular implants, such as heart valves, are formed fromnatural tissue. Illustrative are the heart valves disclosed in U.S. Pat.Nos. 6,719,788 and 5,480,424 to Cox. The disclosed bioprostheses can,however, be affected by gradual calcification, which can, and in manyinstances will, lead to the eventual stiffening and tearing of theimplant.

Many non-bioprosthetic implants are, however, fabricated from variousmetals and polymeric materials, and other exotic materials, such aspyrolytic carbon-coated graphite.

For example, pacemakers, defibrillators, leads, and other similarcardiovascular implants are often fabricated from Ni—Co—Cr alloy,Co—Cr—Mo alloy, titanium, and Ti-6Al-4V alloy, stainless steel, andvarious biocompatible polymeric materials. Artificial heart valves areoften fabricated from various combinations of nylon, silicone, titanium,Teflon™, polyacetal, graphite and pyrolytic carbon.

Artificial hearts and ventricular assist devices are often fabricatedfrom various combinations of stainless steel, cobalt alloy, titanium,Ti-6Al-4V alloy, carbon fiber reinforced composites, polyurethanes,Biolon™, Hemothane™, Dacron™, polysulfone, and other thermoplastics.

Finally, catheters and guide wires are often fabricated from Co—Ni orstainless steel wire. In many instances, the wire is encased in apolymeric material.

As is well known in the art, several major problems are oftenencountered when a medical device (or other device, e.g., trackingapparatus) fabricated from one of the aforementioned materials isimplanted in the body. A major problem that is often encountered afterimplantation of such a device in the body is inflammation of surroundingtissue.

Another major problem is the high incidence of infection.

A further problem that is often encountered after implantation of themedical device in the body is the formation of blood clots(thrombogenesis).

One additional problem that is also often encountered is thedegradation, e.g., corrosion, of medical device leads and, thereby,premature failure of the device after implantation in the body.

Most medical devices are designed to be implanted in the body for anextended period of time. However, when a harsh biological response (orpremature failure of the device) is encountered after implantation, itis often necessary to remove the device through a secondary surgicalprocedure, which can, and in many instances will, result in undesirablepain and discomfort to the patient, and possibly additional trauma tothe adjacent tissue. In addition to the pain and discomfort, the patientmust be subjected to an additional time consuming and complicatedsurgical procedure with the attendant risks of surgery.

There is thus a need to provide medical devices that are configured forimplantation in the body, and substantially reduce or eliminate theharsh biological responses associated with conventional implantedmedical devices, including inflammation, infection and thrombogenesis.

It is therefore an object of the present invention to provide encasementstructures that are configured to encase a medical device therein andthat substantially reduce or eliminate the harsh biological responsesassociated with conventional implanted medical devices, includinginflammation, infection and thrombogenesis, when implanted in the body.

It is another object of the present invention to provide ECM encasementstructures that are configured to encase a medical device therein, andeffectively improve biological functions and/or promote modulatedhealing of adjacent tissue and the growth of new tissue when implantedin the body.

It is another object of the present invention to provide ECM encasementstructures that are configured to encase a medical device therein andadminister one or more pharmacological or therapeutic agents whenimplanted in the body.

It is yet another object of the present invention to provide medicaldevices that are configured for insertion or implantation in the bodyand exhibit enhanced biocompatibility and hemocompatibility wheninserted or implanted therein.

SUMMARY OF THE INVENTION

The present invention is directed to extracellular matrix (ECM)encasement structures and compositions for encasing devices;particularly, medical devices.

In some embodiments of the invention, the ECM encasement structurescomprise a pocket or pouch that is configured to receive a devicetherein. In some embodiments, the device comprises a medical device.

According to the invention, the medical device can comprise, withoutlimitation, a pacemaker, defibrillator, synthetic heart valve,ventricular assist device, artificial heart, physiological sensor,catheter, and associated components, e.g., the electrical leads andlines associated therewith.

In a preferred embodiment, the ECM encasement structures are configuredto encase an entire medical device.

In some embodiments, the ECM encasement structures are also configuredto encase at least a portion of the medical device electrical leads.

In some embodiments of the invention, the ECM encasement structuresinclude lead conduits that are configured to encase the medical deviceleads.

In a preferred embodiment, the ECM encasement structures comprise (or isconstructed of) an ECM composition that includes at least one ECMmaterial.

In other embodiments of the invention, there are provided medicaldevices that are configured for insertion or implantation in the bodyand include at least one coating of an ECM composition; the ECMcomposition similarly including at least one ECM material.

In a preferred embodiment, the ECM material referenced above comprisesmammalian extracellular matrix tissue selected from the group comprisingsmall intestine submucosa (SIS), urinary bladder submucosa (UBS),stomach submucosa (SS), central nervous system tissue, epithelium ofmesodermal origin, i.e. mesothelial tissue, dermal extracellular matrix,subcutaneous extracellular matrix, gastrointestinal extracellularmatrix, i.e. large and small intestines, tissue surrounding growingbone, placental extracellular matrix, omamentum extracellular matrix,cardiac extracellular matrix, e.g., pericardium and/or myocardium,kidney extracellular matrix, pancreas extracellular matrix, lungextracellular matrix, and combinations thereof.

In some embodiments of the invention, the ECM material and, hence ECMencasement structures formed therefrom include at least one additionalbiologically active agent or composition, i.e. an agent that induces ormodulates a physiological or biological process, or cellular activity,e.g., induces proliferation, and/or growth and/or regeneration oftissue.

In some embodiments of the invention, the biologically active agentcomprises a growth factor.

In some embodiments of the invention, the biologically active agentcomprises a cell.

In some embodiments of the invention, the biologically active componentcomprises chitosan.

In some embodiments, the ECM material and, hence ECM encasementstructures formed therefrom include at least one pharmacological agentor composition (or drug), i.e. an agent or composition that is capableof producing a desired biological effect in vivo, e.g., stimulation orsuppression of apoptosis, stimulation or suppression of an immuneresponse, etc.

In some embodiments, the pharmacological agent or composition isselected from the group comprising antibiotics or antifungal agents,anti-viral agents, anti-pain agents, anesthetics, analgesics, steroidalanti-inflammatories, non-steroidal anti-inflammatories,anti-neoplastics, anti-spasmodics, modulators of cell-extracellularmatrix interactions, proteins, hormones, enzymes and enzyme inhibitors,anticoagulants and/or antithrombic agents, DNA, RNA, modified DNA andRNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides,oligonucleotides, polynucleotides, nucleoproteins, compounds modulatingcell migration, compounds modulating proliferation and growth of tissue,and vasodilating agents.

In some embodiments of the invention, the pharmacological agentspecifically comprises an anti-inflammatory agent or composition.

In some embodiments of the invention, the pharmacological agentcomprises a statin, i.e. a HMG-CoA reductase inhibitor.

According to the invention, upon deployment of an encased medical deviceof the invention, i.e. an ECM encasement structure having a medicaldevice therein or a medical device (or instrument) coated with an ECMcomposition of the invention, modulated healing and regeneration oftissue structures with site-specific structural and functionalproperties are effectuated.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the followingand more particular description of the preferred embodiments of theinvention, as illustrated in the accompanying drawings, and in whichlike referenced characters generally refer to the same parts or elementsthroughout the views, and in which:

FIG. 1 is a perspective view of a biventricular (Bi-V) pacemaker;

FIG. 2 is a perspective view of one embodiment of an ECM encasementstructure having the Bi-V pacemaker shown in FIG. 1 encased therein, inaccordance with the invention;

FIG. 3 is a perspective view of an ECM encasement structure,illustrating a folded pre-lamination configuration of an ECM pouchlayer, in accordance with the invention;

FIG. 4 is a front, partial sectional plan view of the ECM encasementstructure shown in FIG. 3, illustrating a laminated ECM pouch layer end,in accordance with the invention;

FIG. 5 is a front, partial sectional plan view of another embodiment ofan ECM encasement structure, in accordance with the invention;

FIGS. 6 and 7 are top plane views of further embodiments of ECMencasement structures, wherein the encasement structures includeelectrical lead conduits; in accordance with the invention;

FIG. 8 is a perspective view of one embodiment of a medical devicehaving an ECM composition coating thereon, in accordance with theinvention; and

FIG. 9 is a front, partial sectional plan view of the coated medicaldevice shown in FIG. 8, in accordance with the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified apparatus, systems, structures or methods as such may, ofcourse, vary. Thus, although a number of apparatus, systems and methodssimilar or equivalent to those described herein can be used in thepractice of the present invention, the preferred apparatus, systems,structures and methods are described herein.

It is also to be understood that, although the present invention isdescribed and illustrated in connection with encased medical devices,the invention is not limited to medical devices. According to theinvention, the extracellular matrix (ECM) structures and compositions ofthe invention can also be employed to encase other devices, including,by way of example, a tracking device.

It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments of the invention only andis not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one having ordinaryskill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein,whether supra or infra, are hereby incorporated by reference in theirentirety.

As used in this specification and the appended claims, the singularforms “a, “an” and “the” include plural referents unless the contentclearly dictates otherwise. Thus, for example, reference to “an active”includes two or more such actives and the like.

Further, ranges can be expressed herein as from “about” or“approximately” one particular value, and/or to “about” or“approximately” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about” or“approximately”, it will be understood that the particular value formsanother embodiment. It will be further understood that the endpoints ofeach of the ranges are significant both in relation to the otherendpoint, and independently of the other endpoint.

It is also understood that there are a number of values disclosedherein, and that each value is also herein disclosed as “about” or“approximately” that particular value in addition to the value itself.For example, if the value “10” is disclosed, then “approximately 10” isalso disclosed. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “10” is disclosed then “less than or equal to 10” as well as“greater than or equal to 10” is also disclosed.

Definitions

The term “medical device”, as used herein, means and includes any deviceconfigured for insertion or implantation in the body of a warm bloodedmammal, including humans and primates; avians; domestic household orfarm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs;laboratory animals, such as mice, rats and guinea pigs; fish; reptiles;zoo and wild animals; and the like. The term “medical device” thusincludes, without limitation, a pacemaker, defibrillator, syntheticheart valve, ventricular assist device, artificial heart, physiologicalsensor, catheter, and associated components thereof, includingelectrical leads and lines associated therewith.

The terms “extracellular matrix”, “ECM” and “ECM material” are usedinterchangeably herein, and mean and include a collagen-rich substancethat is found in between cells in mammalian tissue, and any materialprocessed therefrom, e.g. decellularized ECM. According to theinvention, the ECM material can be derived from a variety of mammaliantissue sources, including, without limitation, small intestine submucosa(SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), centralnervous system tissue, epithelium of mesodermal origin, i.e. mesothelialtissue, dermal extracellular matrix, subcutaneous extracellular matrix,gastrointestinal extracellular matrix, i.e. large and small intestines,tissue surrounding growing bone, placental extracellular matrix,omamentum extracellular matrix, cardiac extracellular matrix, e.g.,pericardium and/or myocardium, kidney extracellular matrix, pancreasextracellular matrix, lung extracellular matrix, and combinationsthereof. The ECM material can also comprise collagen from mammaliansources.

The terms “urinary bladder submucosa (UBS)”, “small intestine submucosa(SIS)” and “stomach submucosa (SS)” also mean and include any UBS and/orSIS and/or SS material that includes the tunica mucosa (which includesthe transitional epithelial layer and the tunica propria), submucosallayer, one or more layers of muscularis, and adventitia (a looseconnective tissue layer) associated therewith.

The ECM material can also be derived from basement membrane of mammaliantissue/organs, including, without limitation, urinary basement membrane(UBM), liver basement membrane (LBM), and amnion, chorion, allograftpericardium, allograft acellular dermis, amniotic membrane, Wharton'sjelly, and combinations thereof.

Additional sources of mammalian basement membrane include, withoutlimitation, spleen, lymph nodes, salivary glands, prostate, pancreas andother secreting glands.

The ECM material can also be derived from other sources, including,without limitation, collagen from plant sources and synthesizedextracellular matrices, i.e. cell cultures.

The term “angiogenesis”, as used herein, means a physiologic processinvolving the growth of new blood vessels from pre-existing bloodvessels.

The term “neovascularization”, as used herein, means and includes theformation of functional vascular networks that can be perfused by bloodor blood components. Neovascularization includes angiogenesis, buddingangiogenesis, intussuceptive angiogenesis, sprouting angiogenesis,therapeutic angiogenesis and vasculogenesis.

The terms “biologically active agent” and “biologically activecomposition” are used interchangeably herein, and mean and include agentthat induces or modulates a physiological or biological process, orcellular activity, e.g., induces proliferation, and/or growth and/orregeneration of tissue.

The terms “biologically active agent” and “biologically activecomposition” thus mean and include, without limitation, the followinggrowth factors: platelet derived growth factor (PDGF), epidermal growthfactor (EGF), transforming growth factor alpha (TGF-alpha), transforminggrowth factor beta (TGF-beta), fibroblast growth factor—2 (FGF-2), basicfibroblast growth factor (bFGF), vascular epithelial growth factor(VEGF), hepatocyte growth factor (HGF), insulin-like growth factor(IGF), nerve growth factor (NGF), platlet derived growth factor (PDGF),tumor necrosis factor alpha (TNA-alpha), and placental growth factor(PLGF).

The terms “biologically active agent” and “biologically activecomposition” also mean and include, without limitation, human embryonicstem cells, fetal cardiomyocytes, myofibroblasts, mesenchymal stemcells, autotransplated expanded cardiomyocytes, adipocytes, totipotentcells, pluripotent cells, blood stem cells, myoblasts, adult sterncells, bone marrow cells, mesenchymal cells, embryonic stem cells,parenchymal cells, epithelial cells, endothelial cells, mesothelialcells, fibroblasts, osteoblasts, chondrocytes, exogenous cells,endogenous cells, stem cells, hematopoietic stem cells, bone-marrowderived progenitor cells, myocardial cells, skeletal cells, fetal cells,undifferentiated cells, multi-potent progenitor cells, unipotentprogenitor cells, monocytes, cardiac myoblasts, skeletal myoblasts,macrophages, capillary endothelial cells, xenogenic cells, allogeniccells, and post-natal stem cells.

The terms “biologically active agent” and “biologically activecomposition” also mean and include, without limitation, the followingbiologically active agents (referred to interchangeably herein as a“protein”, “peptide” and “polypeptide”): collagen (types I-V),proteoglycans, glycosaminoglycans (GAGs), glycoproteins, growth factors,cytokines, cell-surface associated proteins, cell adhesion molecules(CAM), angiogenic growth factors, endothelial ligands, matrikines,cadherins, immuoglobins, fibril collagens, non-fibrallar collagens,basement membrane collagens, multiplexins, small-leucine richproteoglycans, decorins, biglycans, fibromodulins, keratocans, lumicans,epiphycans, heparin sulfate proteoglycans, perlecans, agrins, testicans,syndecans, glypicans, serglycins, selectins, lecticans, aggrecans,versicans, neurocans, brevicans, cytoplasmic domain-44 (CD-44),macrophage stimulating factors, amyloid precursor proteins, heparins,chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A, heparinsulfates, hyaluronic acids, fibronectins, tenascins, elastins,fibrillins, laminins, nidogen/enactins, fibulin I, finulin II,integrins, transmembrane molecules, thrombospondins, ostepontins, andangiotensin converting enzymes (ACE).

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” are used interchangeably herein, and mean and includean agent, drug, compound, composition of matter or mixture thereof,including its formulation, which provides some therapeutic, oftenbeneficial, effect. This includes any physiologically orpharmacologically active substance that produces a localized or systemiceffect or effects in animals, including warm blooded mammals, humans andprimates; avians; domestic household or farm animals, such as cats,dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such asmice, rats and guinea pigs; fish; reptiles; zoo and wild animals; andthe like.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” thus mean and include, without limitation,antibiotics, anti-arrhythmic agents, anti-viral agents, analgesics,steroidal anti-inflammatories, non-steroidal anti-inflammatories,anti-neoplastics, anti-spasmodics, modulators of cell-extracellularmatrix interactions, proteins, hormones, growth factors, matrixmetalloproteinases (MMPS), enzymes and enzyme inhibitors, anticoagulantsand/or antithrombic agents, DNA, RNA, modified DNA and RNA, NSAIDs,inhibitors of DNA, RNA or protein synthesis, polypeptides,oligonucleotides, polynucleotides, nucleoproteins, compounds modulatingcell migration, compounds modulating proliferation and growth of tissue,and vasodilating agents.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” thus include, without limitation, atropine,tropicamide, dexamethasone, dexamethasone phosphate, betamethasone,betamethasone phosphate, prednisolone, triamcinolone, triamcinoloneacetonide, fluocinolone acetonide, anecortave acetate, budesonide,cyclosporine, FK-506, rapamycin, ruboxistaurin, midostaurin,flurbiprofen, suprofen, ketoprofen, diclofenac, ketorolac, nepafenac,lidocaine, neomycin, polymyxin b, bacitracin, gramicidin, gentamicin,oyxtetracycline, ciprofloxacin, ofloxacin, tobramycin, amikacin,vancomycin, cefazolin, ticarcillin, chloramphenicol, miconazole,itraconazole, trifluridine, vidarabine, ganciclovir, acyclovir,cidofovir, ara-amp, foscarnet, idoxuridine, adefovir dipivoxil,methotrexate, carboplatin, phenylephrine, epinephrine, dipivefrin,timolol, 6-hydroxydopamine, betaxolol, pilocarpine, carbachol,physostigmine, demecarium, dorzolamide, brinzolamide, latanoprost,sodium hyaluronate, insulin, verteporfin, pegaptanib, ranibizumab, andother antibodies, antineoplastics, anti VEGFs, ciliary neurotrophicfactor, brain-derived neurotrophic factor, bFGF, Caspase-1 inhibitors,Caspase-3 inhibitors, α-Adrenoceptors agonists, NMDA antagonists, Glialcell line-derived neurotrophic factors (GDNF), pigmentepithelium-derived factor (PEDF), and NT-3, NT-4, NGF, IGF-2.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” further mean and include the following Class I-ClassV antiarrhythmic agents: (Class Ia) quinidine, procainamide anddisopyramide; (Class Ib) lidocaine, phenytoin and mexiletine; (Class Ic)flecainide, propafenone and moricizine; (Class II) propranolol, esmolol,timolol, metoprolol and atenolol; (Class III) amiodarone, sotalol,ibutilide and dofetilide; (Class IV) verapamil and diltiazem) and (ClassV) adenosine and digoxin.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” further mean and include, without limitation, thefollowing antiobiotics: aminoglycosides, cephalosporins,chloramphenicol, clindamycin, erythromycins, fluoroquinolones,macrolides, azolides, metronidazole, penicillins, tetracyclines,trimethoprim-sulfamethoxazole and vancomycin.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” further include, without limitation, the followingsteroids: andranes (e.g., testosterone), cholestanes, cholic acids,corticosteroids (e.g., dexamethasone), estraenes (e.g., estradiol) andpregnanes (e.g., progesterone).

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” can further include one or more classes of narcoticanalgesics, including, without limitation, morphine, codeine, heroin,hydromorphone, levorphanol, meperidine, methadone, oxycodone,propoxyphene, fentanyl, methadone, naloxone, buprenorphine, butorphanol,nalbuphine and pentazocine.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” can further include one or more classes of topical orlocal anesthetics, including, without limitation, esters, such asbenzocaine, chloroprocaine, cocaine, cyclomethycaine,dimethocaine/larocaine, piperocaine, propoxycaine, procaine/novacaine,proparacaine, and tetracaine/amethocaine. Local anesthetics can alsoinclude, without limitation, amides, such as articaine, bupivacaine,cinchocaine/dibucaine, etidocaine, levobupivacaine,lidocaine/lignocaine, mepivacaine, prilocaine, ropivacaine, andtrimecaine. Local anesthetics can further include combinations of theabove from either amides or esters.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” can further include one or more classes of cytotoxicanti-neoplastic agents or chemotherapy agents, including, withoutlimitation, alkylating agents, cisplatin, carboplatin, oxaliplatin,mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide.

Chemotherapy agents can also include, without limitation,antimetabolites, such as purine analogues, pyrimidine analogues andantifolates, plant alkaloids, such as vincristine, vinblastine,vinorelbine, vindesine, podophyllotoxin, etoposide and teniposide,taxanes, such as paclitaxel and docetaxel, topoisomerase inhibitors,such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphateand teniposide, cytotoxic antibiotics, such as actinomyocin, bleomycin,plicamycin, mytomycin and anthracyclines, such as doxorubicin,daunorubicin, valrubicin, idarubicin, epirubicin, and antibodytreatments, such as abciximab, adamlimumab, alamtuzumab, basiliximab,belimumab, bevacizumab, brentuximab vedotin, canakinumab, cetuximab,certolizumab pego, daclizumab, denosumab, eculizumab, efalizumab,gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab,muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab,panitumumab, ranibizumab, rituximab, tocilizumab (atlizumab),tositumomab and trastuzumab.

The terms “anti-inflammatory” and “anti-inflammatory agent” are alsoused interchangeably herein, and mean and include a “pharmacologicalagent” and/or “active agent formulation”, which, when a therapeuticallyeffective amount is administered to a subject, prevents or treats bodilytissue inflammation i.e. the protective tissue response to injury ordestruction of tissues, which serves to destroy, dilute, or wall offboth the injurious agent and the injured tissues.

Anti-inflammatory agents thus include, without limitation, alclofenac,alclometasone dipropionate, algestone acetonide, alpha amylase,amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride,anakinra, anirolac, anitrazafen, apazone, balsalazide disodium,bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetasol propionate, clobetasone butyrate, clopirac, cloticasonepropionate, cormethasone acetate, cortodoxone, decanoate, deflazacort,delatestryl, depo-testosterone, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, mesterolone,methandrostenolone, methenolone, methenolone acetate, methylprednisolonesuleptanate, momiflumate, nabumetone, nandrolone, naproxen, naproxensodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin,oxandrolane, oxaprozin, oxyphenbutazone, oxymetholone, paranylinehydrochloride, pentosan polysulfate sodium, phenbutazone sodiumglycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,stanozolol, sudoxicam, sulindac, suprofen, talmetacin, talniflumate,talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam,tesimide, testosterone, testosterone blends, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, and zomepirac sodium.

The term “pharmacological composition”, as used herein, means andincludes a composition comprising a “pharmacological agent” and/or a“biologically active agent” and/or any additional agent or componentidentified herein.

The term “therapeutically effective”, as used herein, means that theamount of the “pharmacological composition” and/or “pharmacologicalagent” and/or “biologically active agent” administered is of sufficientquantity to ameliorate one or more causes, symptoms, or sequelae of adisease or disorder. Such amelioration only requires a reduction oralteration, not necessarily elimination, of the cause, symptom, orsequelae of a disease or disorder.

The terms “prevent” and “preventing” are used interchangeably herein,and mean and include reducing the frequency or severity of a disease orcondition. The term does not require an absolute preclusion of thedisease or condition. Rather, this term includes decreasing the chancefor disease occurrence.

The terms “treat” and “treatment” are used interchangeably herein, andmean and include medical management of a patient with the intent tocure, ameliorate, stabilize, or prevent a disease, pathologicalcondition, or disorder. The terms include “active treatment”, i.e.treatment directed specifically toward the improvement of a disease,pathological condition, or disorder, and “causal treatment”, i.e.treatment directed toward removal of the cause of the associateddisease, pathological condition, or disorder.

The terms “treat” and “treatment” further include “palliativetreatment”, i.e. treatment designed for the relief of symptoms ratherthan the curing of the disease, pathological condition, or disorder,“preventative treatment”, i.e. treatment directed to minimizing orpartially or completely inhibiting the development of the associateddisease, pathological condition, or disorder, and “supportivetreatment”, i.e. treatment employed to supplement another specifictherapy directed toward the improvement of the associated disease,pathological condition, or disorder.

The terms “patient” and “subject” are used interchangeably herein, andmean and include warm blooded mammals, humans and primates; avians;domestic household or farm animals, such as cats, dogs, sheep, goats,cattle, horses and pigs; laboratory animals, such as mice, rats andguinea pigs; fish; reptiles; zoo and wild animals; and the like.

The term “comprise” and variations of the tern, such as “comprising” and“comprises,” means “including, but not limited to” and is not intendedto exclude, for example, other additives, components, integers or steps.

The following disclosure is provided to further explain in an enablingfashion the best modes of performing one or more embodiments of thepresent invention. The disclosure is further offered to enhance anunderstanding and appreciation for the inventive principles andadvantages thereof, rather than to limit in any manner the invention.The invention is defined solely by the appended claims, including anyamendments made during the pendency of this application, and allequivalents of those claims as issued.

As stated above, it is understood that, although the present inventionis described and illustrated in connection with encased medical devices,the invention is not limited to medical devices. According to theinvention, the extracellular matrix (ECM) structures and compositions ofthe invention can also be employed to encase other devices, including,by way of example, a tracking device.

It is also understood that, although the present invention is describedand illustrated in connection with a pacemaker, the invention is notlimited to the noted medical device. Indeed, as stated above, the ECMencasement structures and compositions of the invention can also beemployed to encase other medical devices, including without limitation,a defibrillator, synthetic heart valve, ventricular assist device,artificial heart, physiological sensor, catheter, and associatedcomponents thereof, including electrical leads and lines associatedtherewith.

As discussed above, in one embodiment, the present invention is directedto extracellular matrix (ECM) encasement structures and compositions forencasing medical devices.

In another embodiment of the invention, there is provided a medicaldevice (or instrument) that includes at least one coating of an ECMcomposition; the ECM composition similarly including at least one ECMmaterial.

According to the invention, upon deployment of an ECM encasementstructure having a medical device therein or a medical device (orinstrument) coated with an ECM composition of the invention to or in asubject, modulated healing and regeneration of tissue structures withsite-specific structural and functional properties are effectuated.

The phrase “modulated healing”, as used herein, and variants of thislanguage generally refer to the modulation (e.g., alteration, delay,retardation, reduction, etc.) of a process involving different cascadesor sequences of naturally occurring tissue repair in response tolocalized tissue damage or injury, substantially reducing theirinflammatory effect. Modulated healing, as used herein, includes manydifferent biologic processes, including epithelial growth, fibrindeposition, platelet activation and attachment, inhibition,proliferation and/or differentiation, connective fibrous tissueproduction and function, angiogenesis, and several stages of acuteand/or chronic inflammation, and their interplay with each other.

For example, in some embodiments, the ECM compositions of the inventionare specifically formulated (or designed) to alter, delay, retard,reduce, and/or detain one or more of the phases associated with healingof damaged tissue, including, but not limited to, the inflammatory phase(e.g., platelet or fibrin deposition), and the proliferative phase.

In some embodiments, “modulated healing” refers to the ability of an ECMcomposition to alter a substantial inflammatory phase (e.g., platelet orfibrin deposition) at the beginning of the tissue healing process. Asused herein, the phrase “alter a substantial inflammatory phase” refersto the ability of an ECM composition to substantially reduce theinflammatory response at an injury site.

In such an instance, a minor amount of inflammation may ensue inresponse to tissue injury, but this level of inflammation response,e.g., platelet and/or fibrin deposition, is substantially reduced whencompared to inflammation that takes place in the absence of an ECMcomposition of the invention.

For example, the ECM compositions discussed herein have been shownexperimentally to delay or alter the inflammatory response associatedwith damaged tissue, as well as excessive formation of connectivefibrous tissue following tissue damage or injury. The ECM compositionshave also been shown experimentally to delay or reduce fibrin depositionand platelet attachment to a blood contact surface following tissuedamage.

In some embodiments of the invention, “modulated healing” refers to theability of an ECM composition of the invention to induce host tissueproliferation, bioremodeling, including neovascularization, e.g.,vasculogenesis, angiogenesis, and intussusception, and regeneration oftissue structures with site-specific structural and functionalproperties.

Accordingly, the ECM compositions discussed herein provide an excellentbioabsorbable cellular interface suitable for use with a medical deviceor surgical instrument.

As indicated above, in one embodiment of the invention, the ECMencasement structures comprise an ECM based pocket or pouch that isconfigured to receive a medical device therein.

According to the invention, the encased medical device and associatedcomponents can comprise, without limitation, a pacemaker, defibrillator,synthetic heart valve, ventricular assist device, artificial heart,physiological sensor, catheter, and the electrical leads and linesassociated therewith.

According to the invention, the entire medical device or a portionthereof can be encased in the ECM encasement structure. Thus, in someembodiments of the invention, the medical device housing and a portionof the device leads are encased in an ECM based pouch. In the notedembodiments, the device leads can also be coated with an ECM compositionof the invention.

In some embodiments of the invention, the ECM encasement structureincludes at least one lead conduit, more preferably, a plurality of leadconduits that are configured to encase the medical device leads.

In a preferred embodiment, the ECM encasement structure comprises (or isconstructed of) an ECM composition that includes at least one ECMmaterial (hereinafter “ECM pouch”). According to the invention, the ECMpouch can comprise various shapes and sizes to accommodate virtually allshapes and sizes of medical devices.

As also indicated above, in other embodiments of the invention, thereare provided medical devices that include at least one coating of an ECMcomposition; the ECM composition similarly including at least one ECMmaterial. According to the invention, the medical devices can similarlyinclude, without limitation, the aforementioned devices and associatedcomponents, as well as surgical instruments.

According to the invention, the ECM material can be derived from variousmammalian tissue sources and methods for preparing same, such asdisclosed in U.S. Pat. Nos. 7,550,004, 7,244,444, 6,379,710, 6,358,284,6,206,931, 5,733,337 and 4,902,508 and U.S. application Ser. No.12/707,427; which are incorporated by reference herein in theirentirety.

The ECM material can also be sterilized via applicant's proprietarysterilization (i.e. Novasterillis®) process, as disclosed in Co-PendingU.S. application Ser. No. 13/480,205; which is expressly incorporatedherein in their entirety.

In a preferred embodiment, the mammalian tissue sources include, withoutlimitation, small intestine submucosa (SIS), urinary bladder submucosa(UBS), stomach submucosa (SS), central nervous system tissue, epitheliumof mesodermal origin, i.e. mesothelial tissue, dermal extracellularmatrix, subcutaneous extracellular matrix, gastrointestinalextracellular matrix, i.e. large and small intestines, tissuesurrounding growing bone, placental extracellular matrix, omamentumextracellular matrix, cardiac extracellular matrix, e.g., pericardiumand/or myocardium, kidney extracellular matrix, pancreas extracellularmatrix, lung extracellular matrix, and combinations thereof. The ECMmaterial can also comprise collagen from mammalian sources.

The ECM material can also be derived from the same or differentmammalian tissue sources, as disclosed in Co-Pending application Ser.Nos. 13/033,053 and 13/033,102; which are incorporated by referenceherein.

As stated above, in some embodiments of the invention, the ECM materialand, hence, ECM encasement structures formed therefrom include at leastone additional biologically active agent or composition, i.e. an agentthat induces or modulates a physiological or biological process, orcellular activity, e.g., induces proliferation, and/or growth and/orregeneration of tissue.

Suitable biologically active agents include any of the aforementionedbiologically active agents, including, without limitation, theaforementioned cells, proteins and growth factors.

In some embodiments, the ECM material and, hence, ECM encasementstructures formed therefrom include at least one pharmacological agentor composition (or drug), i.e. an agent or composition that is capableof producing a desired biological effect in vivo, e.g., stimulation orsuppression of apoptosis, stimulation or suppression of an immuneresponse, etc.

Suitable pharmacological agents and compositions include any of theaforementioned agents, including, without limitation, antibiotics,anti-viral agents, analgesics, steroidal anti-inflammatories,non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics,modulators of cell-extracellular matrix interactions, proteins,hormones, enzymes and enzyme inhibitors, anticoagulants and/orantithrombic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitorsof DNA, RNA or protein synthesis, polypeptides, oligonucleotides,polynucleotides, nucleoproteins, compounds modulating cell migration,compounds modulating proliferation and growth of tissue, andvasodilating agents.

In some embodiments of the invention, the pharmacological agentcomprises an anti-inflammatory agent.

In some embodiments of the invention, the pharmacological agentcomprises a statin, i.e. a HMG-CoA reductase inhibitor. According to theinvention, suitable statins include, without limitation, atorvastatin(Lipitor®), cerivastatin, fluvastatin (Lescol®), lovastatin (Mevacor®,Altocor®, Altoprev®), mevastatin, pitavastatin (Livalo ®, Pitava®),pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin(Crestor®), and simvastatin (Zocor®, Lipex®). Several actives comprisinga combination of a statin and another agent, such asezetimbe/simvastatin (Vytorin®), are also suitable.

Applicant has found that the noted statins exhibit numerous beneficialproperties that provide several beneficial biochemical actions oractivities. The properties and beneficial actions are set forth inApplicant's Co-Pending application Ser. Nos. 13/373,569, filed on Sep.24, 2012 and Ser. No. 13/782,024, filed on Mar. 1, 2013; which areincorporated by reference herein in their entirety.

In some embodiments of the invention, the pharmacological agentcomprises chitosan. As also set forth in detail in Co-Pendingapplication Ser. No. 13/573,569, chitosan also exhibits numerousbeneficial properties that provide several beneficial biochemicalactions or activities.

Additional suitable pharmacological agents and compositions that can bedelivered within the scope of the invention are disclosed in Pat. Pub.Nos. 20070014874, 20070014873, 20070014872, 20070014871, 20070014870,20070014869, and 20070014868; which are expressly incorporated byreference herein in its entirety.

According to the invention, the amount of a pharmacological agent addedto an ECM composition of the invention will, of course, vary from agentto agent. For example, in one embodiment, wherein the pharmacologicalagent comprises dicloflenac (Voltaren®), the amount of dicloflenacincluded in the ECM composition is preferably in the range of 10 μg-75mg.

According to the invention, the biologically active and pharmacologicalagents referenced above can comprise any form. In some embodiments ofthe invention, the biologically active and pharmacological agents, e.g.simvastatin and/or chitosan, comprise microcapsules that provide delayeddelivery of the agent contained therein.

As indicated above, upon deployment of an ECM encasement structure or amedical device (or instrument) coated with an ECM composition of theinvention, modulated healing and regeneration of tissue structures withsite-specific structural and functional properties is effectuated.

Referring now to FIG. 1, there is shown an exemplar implantable medicaldevice; in this instance, a bi-ventricular (Bi-V) pacemaker 20, that canbe encased by an ECM encasement structure of the invention. As is wellknown in the art and illustrated in FIG. 1, the Bi-V pacemaker 20generally includes a pulse generator 21, electrical leads 22 a, 22 b, 22c and lead tips or electrodes 24 a, 24 b, 24 c.

As is also well known in the art, the Bi-V pacemaker 20 is used tomodulate the heart rate of a patient and prevent a life threateningheart dysfunction, e.g. arrhythmia.

The Bi-V pacemaker 20 is typically implanted transveniously in apatient, wherein two (2) electrical leads, i.e. leads 22 a, 22 b, areplaced in a vein and guided to the right atrium and ventricle of theheart. The leads 22 a, 22 b are then attached to the heart muscleproximate the noted heart structures.

The third pacemaker lead, i.e., lead 22 c, is also guided through a veinto the coronary sinus (i.e. a small vein on the back of the heart) andattached to the heart to pace the left ventricle.

Referring now to FIG. 2, there is shown a first embodiment of an ECMencasement structure of the invention 10, having the medical device 20encased therein. As illustrated in FIG. 2, in this embodiment, the ECMencasement structure 10 is configured to encase the entire pacemaker 20and a portion of the leads 22 a, 22 b, 22 c, associated therewith.

The ECM encasement structure 10 generally comprises a pocket or pouch 12having a cavity therein 13. The cavity 13 is sized and configured toreceive and contain a medical device 20 therein.

In a preferred embodiment of the invention, the pouch 12 comprises atleast one layer or sheet of encasement material constructed of an ECMcomposition of the invention. According to the invention, the pouch 12can also include more than one layer of encasement material, e.g. two(2), three (3) encasement layers, etc. The encasement layers can alsocomprise the same material, i.e. ECM material or composition, ordifferent materials or compositions.

In some embodiments of the invention, the ECM composition (or encasementlayer(s)) and, hence, ECM encasement structure 10 formed therefrominclude at least one additional biologically active agent orcomposition, i.e. an agent that induces or modulates a physiological orbiological process, or cellular activity, e.g., induces proliferation,and/or growth and/or regeneration of tissue.

Suitable biologically active agents include any of the aforementionedbiologically active agents, including, without limitation, theaforementioned cells, proteins and growth factors.

In some embodiments, the ECM composition (or encasement layer(s)) and,hence, ECM encasement structure 10 formed therefrom include at least onepharmacological agent or composition (or drug), i.e. an agent orcomposition that is capable of producing a desired biological effect invivo, e.g., stimulation or suppression of apoptosis, stimulation orsuppression of an immune response, etc.

Suitable pharmacological agents and compositions include any of theaforementioned agents, including, without limitation, antibiotics,anti-viral agents, analgesics, and steroidal and non-steroidalanti-inflammatories.

According to the invention, the biologically active and pharmacologicalagents can be incorporated into the ECM composition (and/or material)and/or deposited on the outer surface of an outer encasement layer.

Referring now to FIG. 3, there is shown a perspective view of the ECMencasement structure 10, showing a folded pre-lamination configurationof the encasement layer (denoted “14”). As illustrated in FIG. 3, in thenoted embodiment, the encasement layer 14 comprises a single sheet ofencasement material. To form the pouch 12, the encasement layer 14 isfolded over and laminated on the end 18 (see FIG. 4) and sides 16.

Referring now to FIG. 5, in some embodiments of the invention, the pouch12 similarly comprises one encasement layer 14. However, in the notedembodiments, two (2) sheets of encasement material or layers 15 a, 15 bare employed to form the pouch 12. The layers 15 a, 15 b are laminatedon both ends 19 a, 19 b, as shown in FIG. 5, and sides.

According to the invention, the sides and ends of encasement layers ofthe invention can be laminated by various conventional means, such asstitching, including ECM stitches, stapled, adhesives. The encasementlayers can also be laminated via microneedles and/or microneedlestructures, such as disclosed in Co-Pending application Ser. No.13,686,131.

Referring now to FIGS. 6 and 7, there is shown further embodiments ofECM encasement structures of the invention that are configured to encasemedical devices, as well as the electrical leads associated therewith.Referring first to FIG. 6, in some embodiments, the ECM encasementstructure 30 a similarly comprises a pocket or pouch 31 having a cavitytherein, such as shown in FIG. 2. The cavity is also sized andconfigured to receive and contain a medical device therein.

As illustrated in FIG. 6, the ECM encasement structure 30 a furtherincludes an integral lead conduit 32 a that is configured to receive atleast one medical device, e.g. pacemaker, lead therein.

Referring now to FIG. 7 there is shown another embodiment of an ECMencasement structure 30 b, which similarly comprises a pocket or pouch31 having a cavity 33 therein. As illustrated in FIG. 7, the cavity 33is similarly designed and configured to contain a medical device; inthis instance, pacemaker 20, therein.

In this embodiment, the ECM encasement structure 32 b includes aplurality of lead conduits 32 a, 32 b, 32 c that are configured toreceive a plurality of device electrical leads, in this instance,pacemaker leads 22 a, 22 b, 22 c, therein.

According to the invention, the ECM encasement structures 30 a, 30 b cancomprise any of the aforementioned ECM compositions and/or materials.The ECM compositions and/or materials can similarly include any of theaforementioned biologically active or pharmacological agents.

The lead conduits 32 a, 32 b, 32 c can also be formed from the same ECMcomposition and/or material or a different ECM composition and/ormaterial.

As indicated above, in other embodiments of the invention, there areprovided medical devices that include at least one coating of an ECMcomposition of the invention. According to the invention, the medicaldevices can similarly include, without limitation, the aforementioneddevices and associated components, as well as surgical instruments.

Referring now to FIGS. 8 and 9, there is shown a medical device, e.g.the Bi-V pacemaker, discussed above, having an ECM composition coating42 disposed thereon. According to the invention, at least a portion ofthe medical device is coated with the ECM composition.

In a preferred embodiment, the entire medical device is coated with theECM coating.

In some embodiments, the entire medical device and electrical leadsassociated therewith, e.g. leads 22 a, 22 b, 22 c shown in FIG. 6, arecoated with the ECM composition.

According to the invention, various conventional means can be employedto form the coated biocompatible and hemocompatable medical device (andassociated leads), including spray coating, dipping, etc.

As indicated above, upon deployment of an encased medical device of theinvention, i.e. an ECM encasement structure or the coated medical deviceof the invention, modulated healing and regeneration of tissuestructures with site-specific structural and functional properties areeffectuated.

As will readily be appreciated by one having ordinary skill in the art,the present invention provides numerous advantages compared to prior artvascular endografts. Among the advantages are the following:

-   -   The provision of encasement structures that are configured to        encase a medical device therein and that substantially reduce or        eliminate the harsh biological responses associated with        conventional implanted medical devices, including inflammation,        infection and thrombogenesis, when implanted in the body.    -   The provision of ECM encasement structures that are configured        to encase a medical device therein, and effectively improve        biological functions and/or promote modulated healing of        adjacent tissue and the growth of new tissue when implanted in        the body.    -   The provision of ECM encasement structures that are configured        to encase a medical device therein and administer one or more        pharmacological or therapeutic agents to a subject when        implanted in his/her body.    -   The provision of medical devices that are configured for        insertion or implantation in the body and exhibit enhanced        biocompatibility and hemocompatibility when inserted or        implanted therein.

Without departing from the spirit and scope of this invention, one ofordinary skill can make various changes and modifications to theinvention to adapt it to various usages and conditions. As such, thesechanges and modifications are properly, equitably, and intended to be,within the full range of equivalence of any subsequently profferedclaims.

What is claimed is:
 1. A medical product, comprising: a bioremodelablepouch structure comprising an extracellular matrix (ECM) composition,said ECM composition comprising acellular ECM derived from smallintestine submucosa (SIS), said bioremodelable composition furthercomprising supplemental fibronectin, said acellular ECM comprisingaltered collagen and fibronectin structures, said pouch structure havingan internal region configured to receive a medical device therein; andan implantable medical device disposed in said pouch structure internalregion, said pouch structure being configured to modulate inflammationof damaged biological tissue and induce cell and tissue proliferation,bioremodeling of said damaged biological tissue, and regeneration of newtissue and tissue structures with site-specific structural andfunctional properties, when said pouch structure is delivered to saiddamaged biological tissue.
 2. The medical product of claim 1, whereinsaid ECM composition further comprises an additional biologically activeagent.
 3. The medical product of claim 2, wherein said additionalbiologically active agent comprises fibroblast growth factor-2 (FGF-2).4. The medical product of claim 1, wherein said implantable medicaldevice comprises a medical device selected from the group consisting ofa pacemaker, defibrillator and ventricular assist device.